Members of the genus Chlamydia, a group of obligate intracellular procaryotic pathogens, are important causes of human infectious diseases. Chlamydia pneumoniae recently has been implicated in the initiation and development of atherosclerosis. Chlamydia trachomatis is a major cause of preventable infectious blindness and the leading cause of bacterial sexually transmitted diseases (STD). Upper genital tract complications in females represents a significant women's health issue. Silent pelvic inflammatory disease (PID) can lead to tubal obstructive infertility. This serious disease will require extensive investigation to understand the pathogenic processes that cause irreparable damage of the reproductive tract in women during their child-bearing years. It is important to discern pathologic changes that accompany atherosclerosis, trachoma, PID and tubal obstructive disease as these events actually occur in infected people, but studies involving human populations do not lend themselves well to carefully controlled experimental conditions. Therefore we propose to continue our work using a variety of cell culture systems (human and murine) to study general features of persistent intracellular chlamydial growth which may be common to all chronic chlamydial infections and pursue the murine-C. trachomatis genital tract in vivo model to study the hypothesis that persistent chlamydiae may contribute to the development of upper genital tract disease. This hypothesis will be tested by building on our experience related to the effects of immune response regulated cytokines on chlamydial host cell activation that results in enhanced expression of chlamydial stress response proteins together with new information on the effects of stress response proteins on the disease process. We also will study how these fundamental events in the basic biology of chlamydiae relate to chronic disease as exemplified by upper genital tract infections in mice. The work plan will comprise 4 specific aims, 2 of which are intended to broaden our cell culture knowledge of persistent (stressed) chlamydial growth and 2 of which will apply this knowledge to an in vivo system. Results will lead to increased information concerning how the basic biology of chlamydiae directly impacts the disease process and the development of chronic chlamydial disease.